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Investigation on mechanism for expansion of GM-CSF autoantibody by next generation sequencing.

Research Project

Project/Area Number 24390208
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionNiigata University

Principal Investigator

NAKATA Koh  新潟大学, 医歯学総合病院, 教授 (80207802)

Co-Investigator(Kenkyū-buntansha) TAZAWA Ryushi  新潟大学, 医歯学総合病院, 准教授 (70301041)
NAKAGAKI Kazuhide  日本獣医生命科学大学, 獣医学部, 准教授 (90143635)
INOUE Yoshikazu  近畿中央胸部疾患センター, 臨床研究センター, センター長 (90240895)
NEI Takahito  日本医科大学, 医学部, 助教 (30597670)
TAKIZAWA Jun  新潟大学, 医歯学総合病院, 准教授 (70463990)
YOKOSAKI Yasuyuki  広島大学, 保健センター, 准教授 (80210607)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
Fiscal Year 2014: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2013: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2012: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
Keywords肺胞蛋白症 / 自己免疫疾患 / 肺胞マクロファージ / 自己抗体 / 次世代シークエンス / バイオインフォーマティクス / クラススイッチ / 体細胞超変異 / 抗GM-CSF自己抗体 / 抗体H鎖可変部
Outline of Final Research Achievements

It remains unclear why GM-CSF autoantibody is excessively produced in the patients. By preliminary evaluation using blood lymphocytes obtained from the patients and healthy subjects, we found high affinity IgG type GM-CSF autoantibody producing B cells expanded only in the patients but not in the healthy subjects, although IgM type producing B cells were even between them. It is suggested that class switching and clonal expansion are proceeding in the peripheral lymphnodes in the patients. To elucidate this, we tried to analyze the amino acid sequences of heavy chain variable regions using the next generation sequencing and a bioinformatics tool. Our analysis revealed that CDR1,2,and 3 amino acid sequences were variable and even in IgM clones but some specific sequences were exclusively used in IgG-type clones, suggesting oligo clonal expansion of IgG-type GM-CSF autoantibody clones in the patients.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (24 results)

All 2014 2013 2012

All Journal Article (19 results) (of which Peer Reviewed: 19 results,  Open Access: 9 results,  Acknowledgement Compliant: 7 results) Presentation (4 results) Book (1 results)

  • [Journal Article] Novel aspects on the pathogenesis of Mycoplasma pneumoniae pneumonia and therapeutic implications.2014

    • Author(s)
      Saraya T, Kurai D, Nakagaki K, Sasaki Y, Niwa S, Tsukagoshi H, Nunokawa H, Ohkuma K, Tsujimoto N, Hirao S, Wada H, Ishii H, Nakata K, Kimura H, Kozawa K, Takizawa H, Goto H.
    • Journal Title

      Front Microbiol

      Volume: 5 Pages: 410-410

    • DOI

      10.3389/fmicb.2014.00410

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Prenatal molecular diagnosis of X-linked hydrocephalus via a silent C924T mutation in the L1CAM gene2014

    • Author(s)
      Serikawa T, Nishiyama K, Tohyama J, Tazawa R, Goto K, Kuriyama Y, Haino K, Kanemura Y, Yamasaki M, Nakata K, Takakuwa K, Enomoto T.
    • Journal Title

      Congenit Anom (Kyoto)

      Volume: 54 Issue: 4 Pages: 243-245

    • DOI

      10.1111/cga.12069

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Up-regulation of cluster of differentiation (CD) 11b expression on the surface of canine granulocytes with human granulocyte-macrophage colony-stimulating factor (GM-CSF).2014

    • Author(s)
      Nakagaki K, Nunomura Y, Uchida K, Nakata K, Tazawa R.
    • Journal Title

      J Vet Med Sci

      Volume: 76(8) Pages: 1173-6

    • NAID

      130004432194

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan2014

    • Author(s)
      Haruyuki Ishii, John F Seymour, Ryushi Tazawa, Yoshikazu Inoue, Naoyuki Uchida, Aya Nishida, Yoshihito Kogure, Takeshi Saraya, Keisuke Tomii, Toshinori Takada, Yuko Itoh, Masayuki Hojo, Toshio Ichiwata, Hajime Goto, Koh Nakata
    • Journal Title

      BMC Pulmonary Medicine

      Volume: 14: 37 Issue: 1 Pages: 1471-2466

    • DOI

      10.1186/1471-2466-14-37

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Low concentrations of recombinant granulocyte macrophage-colony stimulating factor derived from Chinese hamster ovary cells augments long-term bioactivity with delayed clearance in vitro2014

    • Author(s)
      Hashimoto A, Tanaka T, Itoh Y, Yamagata A, Kitamura N, Tazawa R, Nakagaki K, Nakata K.
    • Journal Title

      Cytokine

      Volume: 68 Issue: 2 Pages: 118-126

    • DOI

      10.1016/j.cyto.2014.03.009

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis2014

    • Author(s)
      Uchida K, Nakata K, Carey B, Chalk C, Suzuki T, Sakagami T, Koch DE, Stevens C, Inoue Y, Yamada Y, Trapnell BC.
    • Journal Title

      J Immunol Methods

      Volume: 402 Issue: 1-2 Pages: 57-70

    • DOI

      10.1016/j.jim.2013.11.011

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] CYFRA 21-1 as a disease severity marker for autoimmune pulmonary alveolar proteinosis.2014

    • Author(s)
      Arai T, Inoue Y, Sugimoto C, Inoue Y, Nakao K, Takeuchi N, Matsumuro A, Hirose M, Nakata K, Hayashi S.
    • Journal Title

      Respirology

      Volume: 19 Issue: 2 Pages: 246-252

    • DOI

      10.1111/resp.12210

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy.2014

    • Author(s)
      Tazawa R, Inoue Y, Arai T, Takada T, Kasahara Y, Hojo M, Ohkouchi S, Tsuchihashi Y, Yokoba M, Eda R, Nakayama H, Ishii H, Nei T, Morimoto K, Nasuhara Y, Ebina M, Akira M, Ichiwata T, Tatsumi K, Yamaguchi E, Nakata K.
    • Journal Title

      Chest

      Volume: 145 Issue: 4 Pages: 729-737

    • DOI

      10.1378/chest.13-0603

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Clinical features of three cases with pulmonary alveolar proteinosis secondary to myelodysplastic syndrome developed during the course of Behçet's disease.2013

    • Author(s)
      Handa T, Nakatsue T, Baba M, Takada T, Nakata K, Ishii H
    • Journal Title

      Respiratory Investigation

      Volume: 52 Issue: 1 Pages: 75-79

    • DOI

      10.1016/j.resinv.2013.05.005

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Light chain (κ/λ) ratio of GM-CSF autoantibodies is associated with disease severity in autoimmune pulmonary alveolar proteinosis.2013

    • Author(s)
      Nei T, Urano S, Itoh Y, Kitamura N, Hashimoto A, Tanaka T, Motoi N, Kaneko C, Tazawa R, Nakagaki K, Arai T, Inoue Y, Nakata K.
    • Journal Title

      Clin Immunol

      Volume: 149(3) Issue: 3 Pages: 357-364

    • DOI

      10.1016/j.clim.2013.10.002

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Serum VEGF-D concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response:a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial.2013

    • Author(s)
      Young L, Lee HS, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Downey GP, Swigris JJ, Taveira-DaSilva AM, Krischer JP, Trapnell BC, McCormack FX; MILES Trial Group.
    • Journal Title

      The Lancet Respiratory Medicine.

      Volume: 1(6) Issue: 6 Pages: 445-452

    • DOI

      10.1016/s2213-2600(13)70090-0

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mycoplasma pneumoniae extract induces an IL-17-associated inflammatory reaction in murine lung: Implication for mycoplasmal pneumonia.2013

    • Author(s)
      Kurai D, Nakagaki K, Wada H, Saraya T, Kamiya S, Fujioka Y, Nakata K,Takizawa H, Goto H
    • Journal Title

      Inflammation

      Volume: 36(2) Issue: 2 Pages: 285-293

    • DOI

      10.1007/s10753-012-9545-3

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 肺胞蛋白症に見られる易感染性2013

    • Author(s)
      赤坂圭一、中田光
    • Journal Title

      化学療法の領域

      Volume: 29(12) Pages: 28-35

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 肺胞蛋白症とGM-CSF自己抗体2013

    • Author(s)
      中田光
    • Journal Title

      検査と技術

      Volume: 41(13) Pages: 1224-1229

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 自己培養骨膜シートを用いた歯槽骨再生研究-データをどのように評価するか-2013

    • Author(s)
      奥田一博、吉江弘正、川瀬知之、 中田光
    • Journal Title

      新潟医学会雑誌(別刷)

      Volume: 127(7) Pages: 349-354

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IgM-type GM-CSF autoantibody is etiologically a bystander but associated with IgG-type autoantibody production in autoimmune pulmonary alveolar proteinosis.2012

    • Author(s)
      Nei T, (10名略)Tazawa R, Nakata K.
    • Journal Title

      Am J Physiol Lung Cell Mol Physiol.

      Volume: 302(9) Issue: 9 Pages: 1959-64

    • DOI

      10.1152/ajplung.00378.2011

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Runx1 deficiency in CD4+ T cells causes fatal autoimmune inflammatory lung disease due to spontaneous hyperactivation of cells.2012

    • Author(s)
      Wong WF, Kohu K, Nakamura A, Ebina M, Kikuchi T, Tazawa R, Tanaka K, Kon S, Funaki T, Sugahara-Tobinai A, Looi CY, Endo S, Funayama R, Kurokawa M, Habu S, Ishii N, Fukumoto M, Nakata K, Takai T, Satake M.
    • Journal Title

      J Immunol.

      Volume: 188(11) Pages: 5408-5420

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bilateral Peripheral Infiltrates Refractory to Immunosuppressants were Diagnosed as Autoimmune Pulmonary Alveolar Proteinosis and Improved by Inhalation of Granulocyte/Macrophage-Colony Stimulating Factor2012

    • Author(s)
      Satoh H, Tazawa R, (4名略), Nakata K, Nukiwa T.
    • Journal Title

      Internal Medicine

      Volume: 51 Issue: 13 Pages: 1737-1742

    • DOI

      10.2169/internalmedicine.51.6093

    • NAID

      130002062188

    • ISSN
      0918-2918, 1349-7235
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 肺胞蛋白症の十年史2012

    • Author(s)
      中田 光
    • Journal Title

      呼吸

      Volume: 31(9) Pages: 845-848

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] Pulmonary Alveolar Proteinosis (PAP) And Inhaled Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) Therapy-Clinical Features Predicting Recurrence.2012

    • Author(s)
      R. Tazawa, T. Arai, T. Takada, Y. Kasahara, Y. Tsuchihashi, T. Nei, M. Hojo, H. Nakayama, M. Yokoba, H. Ishii, R. Eda, Y. Nasuhara, M. Ebina, M. Akira, E. Yamaguchi, Y. Inoue, K. Nakata.
    • Organizer
      Meet The Professor Meeting.
    • Place of Presentation
      ドイツ(招待講演)
    • Year and Date
      2012-06-23
    • Related Report
      2012 Annual Research Report
  • [Presentation] IgM Type GM-CSF Autoantibody is Etiologically a Bystander but Maybe Involved in Development of IgG Type Autoantibody in Autoimmune Pulmonary Alveolar Proteinosis.2012

    • Author(s)
      Nakata K, Nei T, Motoi N, Urano S, Tazawa R, Kanako C, Nakagaki K, Suzuki M, Takizawa J, Azuma A.
    • Organizer
      American Thoracic Society Annual Meeting.
    • Place of Presentation
      アメリカ
    • Year and Date
      2012-05-23
    • Related Report
      2012 Annual Research Report
  • [Presentation] Evidence for Permeation of IgG type GM-CSF Autoantibody from the Circulation to the Lung in Autoimmune Pulmonary Alveolar Proteinosis.2012

    • Author(s)
      Urano S, Akasaka K, Nei T, Motoi N, Tazawa R, Nakata K.
    • Organizer
      American Thoracic Society Annual Meeting.
    • Place of Presentation
      アメリカ
    • Year and Date
      2012-05-23
    • Related Report
      2012 Annual Research Report
  • [Presentation] Repertoire Analysis of GM-CSF Autoantibody mRNA by Next Generation Sequencing In Autoimmune Pulmonary Alveolar Proteinosis.2012

    • Author(s)
      Nakata K, Nei T, Motoi N, Urano S, Tazawa R, Nakagaki K, Suzuki M, Takizawa J, Azuma A.
    • Organizer
      American Thoracic Society Annual Meeting.
    • Place of Presentation
      アメリカ
    • Year and Date
      2012-05-23
    • Related Report
      2012 Annual Research Report
  • [Book] 大学病院などの再生医療を支える細胞プロセッシング室運営マニュアル2012

    • Author(s)
      井上典子, 梶正美, 小神晴美, 渡辺真理, 関根優, 白山早起, 藤本陽子, 瀧澤淳, 牧口智夫, 布施一郎, 中田光
    • Total Pages
      142
    • Publisher
      株式会社ウイネット
    • Related Report
      2012 Annual Research Report

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Published: 2012-04-24   Modified: 2019-07-29  

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